NF-kappaB includes a family of signal-activated transcription factors that normally regulate responses to injury and infection but which are aberrantly activated in many carcinomas. Cumulative evidence implicates NF-kappaB in cell survival, inflammation, angiogenesis, spread and therapeutic resistance during tumor development, progression and metastasis of carcinomas. Non-specific natural and synthetic agents that inhibit NF-kappaB have demonstrated activity and safety in prevention or therapy. NF-kappaB-activating kinases are under investigation for targeted prevention and therapy of carcinoma. As part of The Cancer Genome Atlas group characterizing head and neck cancer, we have identified components of PI3K and TNF pathway as candidate genetic drivers for aberrant NF-kB activation and defects in death signaling. A clinical trial with mTOR inhibitor rapamycin has completed accrual and is under data analysis. Studies using a genome wide RNAi screen employing NF-kB reporter lines have identified potential drug targets promoting NF-kB activation.